Patent Application
20180019034
The present disclosure relates generally to the generation of unstable, i.e., radioactive, nuclear isotopes, and more particularly to a system and method for generating the medical radionuclide nitrogen-13 (13N) via the gamma-ray-induced isotopic reaction, 14N(γ,n)13N.
Nitrogen-13 (13N), used in the form of the tracer 13N-ammonia (NH3), is a valuable positron-emitting radionuclide commonly used for cardiac positron emission tomography (PET) imaging of the myocardium under rest or pharmacologic stress conditions to evaluate myocardial perfusion in patients with suspected or existing coronary artery disease or small-vessel disease. 13N-ammonia can also be utilized to measure blood flow in other parts of the body, such as the liver, kidney, brain and malignant tumors.
When used for cardiac PET imaging, the 13N diffuses rapidly from the blood into myocardial cells. Some of the 13N-ammonia is synthesized into 13N-glutamine and becomes metabolically trapped in the myocardium. Since the myocardial uptake is proportional to the blood flow, 13N-ammonia is a good myocardial perfusion agent for the detection of coronary artery disease.
13N-ammonia has a short half-life (9.97 minutes) and decays by positron emission (100%) resulting in the production of two (2) 511 keV gamma-rays via the annihilation process.
One method that has been used to produce the 13N used in nuclear medicine utilizes the 16O(p,α)13N nuclear reaction via proton irradiation of 16O. Another method involves irradiation of H2O in the presence of 5-10 millimolar ethanol by protons from cyclotrons having energies greater than 11 MeV. The proton bombardment produces 13N-ammonia as the major radionuclide, but also 15O by the 16O(p,pn)15O nuclear reactions. The 13N-ammonia is held for 10 minutes which allows the 15O (half-life 2.04 minutes) to decay to less than 5% by time of delivery. Trace amounts of (18F) fluoride ions are also produced from the 0.2% naturally occurring 18O-water by the 18O(p,n)18F nuclear reactions. These traces of fluoride ions are removed by the anion exchange resin used for purification of 13N-ammonia. A half-life measurement is performed for each batch of 13N-ammonia, which results in a measurement between 9.5-10.5 min. Other production methods and additional details are described in Hell J Nucl Med 2009; 12(3): 248-250, which is incorporated herein by reference.
Due to the short half-life of 13N, it is not possible to stock-pile the 13N, so a large quantity of 13N has to be produced with expensive cyclotrons using the current production methods. Several large production facilities currently are regionally dispersed to serve patients in all areas of the country. However, cyclotrons not only have huge initial setup cost, but also are expensive to maintain and operate. Accordingly, there is a need for a method for producing 13N-ammonia that utilizes a very inexpensive, on-demand production system and thereby eliminates the need for large and expensive cyclotron facilities.
The present disclosure is directed to a system and method for the production of 13N-ammonia from nitrogen-14 (14N) that includes loading a 14N target into an irradiation chamber, using an incident beam of electrons impinging on a high-Z material to produce an intense collimated bremsstrahlung (photon beam) and directing the intense collimated photon beam to irradiate the 14N target. 13N is produced through the 14N(γ,n)13N nuclear reaction.
Methods for producing 13N-ammonia are disclosed. In the first, the 14N of the 14N target may be in the form of liquid ammonia or ammonia gas, which is directly irradiated to form 13N-ammonia. In the second, the 14N target may be in the form of liquid nitrogen (N2), with the 13N produced then converted to 13N-ammonia via a conventional synthesis process, such as the Haber process.
In contrast to the production of 13N-ammonia through the 16O(p,α)13N nuclear reaction using a cyclotron to accelerate charged particles, the method of the instant disclosure utilizes high energy photons to produce 13N-ammonia and so does not require a cyclotron. Instead, a compact electron accelerator introduces the required energy into the system by generating an incident beam of high energy electrons impinging onto a high-Z material to produce an intense photon beam. Compact electron accelerators are much less expensive than cyclotrons to procure,—to install, and to maintain and operate.
Electrons impinging on the high-Z converter target generates photons to form the gamma-ray beam. Preferably the energy of most of the photons generated is above the threshold of the 14N(γ,n)13N nuclear reaction, which is about 10.5 MeV. In some embodiments, the photons generated can have an energy up to about 30 MeV. In some embodiments, the photons generated can have an energy up to about 25 MeV or up to about 20 MeV. In some embodiments, photons having an energy in the range of about 10.5 MeV to about 30 MeV, about 10.5 MeV to about 25 MeV, or about 10.5 MeV to about 20 MeV can create the isotope 13N, while avoiding the production of undesirable isotopes.
The production of 13N from the 14N(γ,n)13N reaction is shown in the graph of
An object of the present disclosure is to provide a system and method that produces —N-ammonia used in nuclear medicine.
An additional object of the present disclosure is to provide a —N-ammonia production system and method that produces the medical isotope 13N without the usage of a cyclotron.
These and other objects, features, and advantages of the present disclosure will become more readily apparent from the attached drawings and from the detailed description of the embodiments which follow.
Embodiments of the disclosure will hereinafter be described in conjunction with the appended drawings, provided to illustrate and not to limit the disclosure, where like designations denote like elements.
Like reference numerals refer to like parts throughout the several views of the drawings.
The present disclosure is directed to a system and method for the production of 13N-ammonia (13NH3) by converting nitrogen-14 (14N) to nitrogen-13 (13N) utilizing the 14N(γ,n)13N reaction. Some embodiments are directed to a first method for producing 13NH3 through direct irradiation of liquid ammonia or ammonia gas (
The electron accelerator 15 is a compact, high-power electron accelerator that generates an electron beam 20 with electrons having an energy above about 10.5 MeV, which is the photon energy threshold of the 14N(γ,n)13N reaction. In some embodiments, the electrons may have an energy up to about 30 MeV. The intensities of the bremsstrahlung spectra produced by this type of relativistic electron beam are all forward-peaking and sometimes referred to as a “radiation cone,” which is the collimated photon (gamma-ray) beam 30 in
The appropriate electron accelerator 15 is chosen based on considerations of economics and technical requirements for successful process implementation. For example, a suitable electron accelerator is the Varian CLINAC 2100C high energy electron linear accelerator, having an energy of about 30 MeV, which can deliver about 125 Gray of radiation per minute while delivering an electron current >1 milliamp.
The high-Z converter 25 is placed in the path of the incident electron beam 20 to convert the relativistic electrons via the (e−,γ) reaction with the photon maximum energy roughly equal to the maximum incident electron energy. Although any of a number of high-Z materials may be used, exemplary high-Z materials are uranium (U), tantalum (Ta), and tungsten (W). The high-Z converter 25 may be in a solid form (such as a plate or sheet), may be multiple solid pieces (such as multiple sheets), or may be in the form of a mesh or matrix array of material. The conversion (production) efficiency of bremsstrahlung for electrons with a thin high-Z converter and energy of about 30 MeV is about 70%. About 30% of the produced high energy photons (or hard x-rays, or gamma-rays) are contained within a narrow solid angle of about 5 steradians.
The target sample holder 35 may be configured to receive a predetermined volume of the liquid ammonia or ammonia gas to be irradiated. In some embodiments, the liquid ammonia may be anhydrous liquid ammonia. The sample holder 35 preferably is positioned within the narrow solid angle of about 5 steradians of the forward-peaking bremsstrahlung cone of photons. In some embodiments, a 3 cc vial may be used to hold the target, but vials of other sizes can also be used. Optionally, in some embodiments, input/output piping 28 may be included to allow introduction and extraction of the target material into and out of the sample holder 35.
With reference to
In some embodiments, the cross-sectional area of the sample holder 35 is 1 cm2; the length is 3 cm; and the volume is 3 cc. Using this configuration and the output from the electron accelerator of 1 milliampere of current, the output of the system would be 6.24×1015 electrons/second. The photon flux (the number of photons above 10 MeV/cm2/second) produced from a 25 MeV electron beam using a converter imparting onto a sample with a cross sectional area of 1 cm2 that is placed at a distance of 1 meter from the converter is equal to (0.7)×(0.3)×(0.1)×(6.24×1015) photons/cm2/second, which is 1.3×1014 photons/cm2/second. Since the 14N(γ,n)13N nuclear reaction cross-section has an average of about 10 millibarns between 10 MeV and 25 MeV, the total number of 13N nuclei that could be produced in one second within the liquid ammonia sample is equal to [(photon flux)×(density)×(Avogadro number)×(reaction cross-sections)×(thickness of sample)×(atomic weight)], which equals to about 1×1011 13N nuclei produced per sec. Therefore, 7.2×1010 13N nuclei can be produced in 1 second with a 1 mA, 25 MeV electron beam through a thin high-Z converter (such as 4 mm Tungsten) with a sample holder 35 that is 3 cm long with a cross-sectional area of 1 cm2, placed at 1 meter away from the converter.
Electrons are generated (step 71) by the electron accelerator components 15 as shown in
The irradiated ammonia (having a portion of the nitrogen being 14N and a portion being 13N) is removed from the nitrogen target sample holder 35. In embodiments where ammonia gas is used as ammonia target, the irradiated ammonia gas can be converted to irradiate liquid ammonia by further passing through a condenser. In some embodiments, the irradiated ammonia gas can also pass through a condenser and a compressor.
In some embodiments, the irradiated liquid ammonia can undergo a purification process (step 79), where it is filtered, purified and prepared (step 79) for use. The purified ammonia is packaged and transported to the location of use, which is usually within the same facility, due to the short half-life of 13N. In some embodiments, before or after transporting, the liquid ammonia is diluted to an appropriate volume with a sodium solution. Once the dose rate is checked, the dose of 13N-ammonia can be administered to the patient.
By-products are formed by the competing reaction 14N(γ,p)13C 78 and from neutrons generated from deuterium (step 76). Though deuterium has only a 0.01% natural abundance, its low photoneutron threshold of 2.22 MeV makes it an important potential neutron source when liquid ammonia is used to produce 13N-ammonia. The photoneutrons produced through the 2H(γ,n)1H nuclear reaction 74 will interact with the 14N atoms via the following nuclear reactions: 14N(n,α)11B, 14N(n,p)14C; 14N(n,γ)15N; and 14N(n,2n)13N. The 14N(n,α)11B has a threshold at about 1 MeV and produces 11B. The 14N(n,p)14C nuclear reaction also has a low threshold and has a cross-section equivalent to the cross-section of the 14N(n,α)11B reaction at 1 MeV. However, both 11B and 14C are insoluble in liquid ammonia, so these impurities can be removed by micro-filtration in the purify and prepare operation of step 79. The 14N(n,γ)15N nuclear reaction produces 15N, which is a stable isotope of nitrogen that does not affect the chemical and physical properties of 13N-ammonia, so removal of 15N is unnecessary. The 14N(n,2n)13N nuclear reaction produces 13N, which is the desired isotope, and thus it will merely aid in producing a higher concentration of the desirable 13N-ammonia product.
The irradiated liquid nitrogen (step 95) (including 14N and 13N) is removed from the sample holder 35, and then converted to liquid ammonia (step 99). In some embodiments, conversion of liquid nitrogen to liquid ammonia in step 99 may be accomplished using the Haber process. The liquid nitrogen (from step 95) is converted to nitrogen gas, and then combined with hydrogen gas in 1:3 ratio by volume. The gas mixture is compressed and introduced into a reaction chamber, where the reaction takes place at a temperature of about 400 to about 450° C., a pressure of about 200 to about 250 atm, and in the presence of a catalyst. The catalyst may be osmium, platinum, iron (such as prepared by reducing magnetite (Fe3O4)), or ruthenium-based catalyst or other known Haber catalyst. After the reaction, the resultant gas is cooled and condensed into liquid ammonia. In some embodiments, the resultant ammonia gas may also be compressed during the process of conversion to liquid ammonia.
In some embodiments, the resultant liquid ammonia can undergo a purification process (step 79), where it is filtered, purified and prepared for use. The purified ammonia is packaged and transported to the location of use, which is usually within the same facility, due to the short half-life of 13N. In some embodiments, before or after transporting, the liquid ammonia is diluted to an appropriate volume with a sodium solution. Once the dose rate is checked, the dose of 13N-ammonia can be administered to the patient.
In this second production method depicted in
Since many modifications, variations, and changes in detail can be made to the described preferred embodiments of the disclosure, it is intended that all matters in the foregoing description and shown in the accompanying drawings be interpreted as illustrative and not in a limiting sense. Thus, the scope of the disclosure should be determined by the appended claims and their legal equivalents.
Any and all applications for which a foreign or domestic priority claim is identified in the Application Data Sheet as filed with the present application are hereby incorporated by reference under 37 CFR 1.57.
| Number | Date | Country | |
|---|---|---|---|
| 62361758 | Jul 2016 | US |
